E.M. Baerveldt (Ewout M.)http://repub.eur.nl/ppl/36236/
List of Publicationsenhttp://repub.eur.nl/eur_signature.pnghttp://repub.eur.nl/
RePub, Erasmus University RepositoryUstekinumab improves psoriasis-related gene expression in noninvolved psoriatic skin without inhibition of the antimicrobial responsehttp://repub.eur.nl/pub/56806/
Wed, 01 May 2013 00:00:01 GMT<div>E.M. Baerveldt</div><div>A.J. Onderdijk</div><div>D. Kurek</div><div>M. Kant</div><div>E. Florencia</div><div>A.S. Ijpma</div><div>P.J. van der Spek</div><div>J. Bastiaans</div><div>P. Jansen</div><div>J.W.J. van Kilsdonk</div><div>J.D. Laman</div><div>E.P. Prens</div>
Background Ustekinumab is a fully human anti-p40 monoclonal antibody which neutralizes interleukin (IL)-12 and IL-23, thereby interfering with T-helper (Th)1/Th17 pathways and keratinocyte activation, and is highly effective in the treatment of psoriasis. During ustekinumab treatment, some of our patients noticed reduced koebnerization of noninvolved skin and less new plaque formation. Objectives To determine whether ustekinumab improves psoriasis-related gene expression and tape-strip responses in noninvolved skin. Methods Before and 4 weeks after ustekinumab treatment, noninvolved skin was tape-stripped. After 5 h, biopsies were taken from untouched and tape-stripped skin. The mRNA expression of psoriasis-related markers such as NGF, GATA3 and IL-22RA1, and several antimicrobial peptides (AMP) was quantified. Leucocyte counts and a broad range of inflammatory serum proteins were analysed to gain insight into the systemic alterations. Results Four weeks following a single ustekinumab injection, NGF showed a significant decrease, whereas GATA3 and IL-22RA1 expression increased, indicative of reduced responsiveness to epidermal triggering. This was accompanied by an increase of the inflammation-related serum proteins GPNMB, MST1 and TRADD. The baseline and tape-strip-induced mRNA expression of the AMP human β-defensin-2 (hBD-2), S100A7 and LL-37 remained unaltered. Clinically, after 4 weeks, eight out of 11 patients showed a 50% psoriasis area and severity index (PASI) improvement, which was accompanied by a significant reduction in serum hBD-2 levels. No changes were noted in total leucocytes, C-reactive protein and erythrocyte sedimentation rate. Conclusions These findings indicate that ustekinumab reduces psoriasis-related gene expression in noninvolved psoriatic skin, making it more resistant to exogenous triggering, without disturbing its antimicrobial response. In parallel, ustekinumab modulates important circulating inflammation-related proteins.Successful long-term triple disease control by ustekinumab in a patient with Behçet's disease, psoriasis and hidradenitis suppurativahttp://repub.eur.nl/pub/40807/
Mon, 01 Apr 2013 00:00:01 GMT<div>E.M. Baerveldt</div><div>J.H. Kappen</div><div>H.B. Thio</div><div>J.A.M. van Laar</div><div>P.M. van Hagen</div><div>E.P. Prens</div>
Psoriasis: Molecular targets of denervation and therapy http://repub.eur.nl/pub/38925/
Wed, 13 Feb 2013 00:00:01 GMT<div>E.M. Baerveldt</div>
In this thesis global transcriptomic effects of denervation were analyzed in unique cases showing unilateral resolution of psoriasis occurred following surgical denervation (chapter 2). In our studies, we focused on the epidermis, as this forms the main innate defence barrier of the skin. We analysed global transcriptomic effects of surgical denervation in a murine psoriasiform model (chapter 3). Because the contribution of neuromediators to innate defence is mostly unknown, we investigated the effects of SP, CGRP, and VIP on the epidermal expression of TLR and host defence peptides in an ex vivo skin explant model (chapter 4). The molecular epidermal targets of recombinant IL-4 in ex vivo stimulated biopsies from psoriatic and healthy skin were investigated (chapter 5). Furthermore, the effect of the biologic ustekinumab (anti IL-12/IL-23) on epidermal molecular markers of innate defence in uninvolved skin of patients with psoriasis was investigated (chapter 6).
The following main conclusions were drawn: Denervation affected genes involved in epidermal barrier function, and TLR function, as the inflammatory response to the TLR7 ligand imiquimod is prevented in denervated skin. Denervation inhibited cutaneous CGRP expression and prevented the enhanced expression of CGRP by imiquimod. Ex vivo stimulation of skin with GCRP results in enhanced expression of epidermal TLR9. Established treatments reach beyond the dermal infiltrate and also target keratinocytes: IL-4 and ustekinumab therapy increase GATA3, which is a transcription factor critical for epidermal homeostasis, and down-regulate NGF expression, which is linked to inflammatory conditions.
Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathwayshttp://repub.eur.nl/pub/33387/
Fri, 01 Jul 2011 00:00:01 GMT<div>E. Rácz</div><div>E.P. Prens</div><div>D. Kurek</div><div>M. Kant</div><div>D. de Ridder</div><div>S. Mourits</div><div>E.M. Baerveldt</div><div>Z. Özgür</div><div>W.F.J. van IJcken</div><div>J.D. Laman</div><div>F.J.T. Staal</div><div>L. van der Fits</div>
Narrow-band ultraviolet-B (NB-UVB) phototherapy is an effective treatment for psoriasis. The molecular mechanisms underlying its efficacy are incompletely understood. To identify NB-UVB-induced molecular pathways that may account for its anti-inflammatory efficacy, gene expression profiling was performed using epidermal RNA from lesional and nonlesional skin from patients with psoriasis undergoing NB-UVB therapy. Downregulation of Th17 signaling pathway was observed during NB-UVB therapy in psoriatic epidermis. Strong inhibition of the Th17 pathway by UVB was confirmed in an ex vivo organ culture system by demonstrating reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation and Β-defensin-2 production. These results were further substantiated by demonstrating that NB-UVB inhibited the Th17-dependent psoriasis-like dermatitis in mice. Other pathways affected by NB-UVB therapy include the IFN signaling pathway, epidermal differentiation, and other well-known therapeutic targets in psoriasis, such as the glucocorticoid, vitamin D, peroxisome proliferator-activated receptor, and IL-4 signaling pathways. In conclusion, clinical improvement of psoriasis by NB-UVB is linked to suppression of Th17 and type I and type II IFN signaling pathways, which are critical in the pathogenesis of the disease. Our results show that clinically effective NB-UVB therapy is based on suppression of a broad range of important molecular pathways in psoriatic skin. GATA3 expression is decreased in psoriasis and during epidermal regeneration; induction by narrow-band UVB and IL-4http://repub.eur.nl/pub/26372/
Mon, 23 May 2011 00:00:01 GMT<div>E. Rácz</div><div>D. Kurek</div><div>M. Kant</div><div>E.M. Baerveldt</div><div>E. Florencia</div><div>S. Mourits</div><div>D. de Ridder</div><div>J.D. Laman</div><div>L. van der Fits</div><div>E.P. Prens</div>
Psoriasis is characterized by hyperproliferation of keratinocytes and by infiltration of activated Th1 and Th17 cells in the (epi)dermis. By expression microarray, we previously found the GATA3 transcription factor significantly downregulated in lesional psoriatic skin. Since GATA3 serves as a key switch in both epidermal and T helper cell differentiation, we investigated its function in psoriasis. Because psoriatic skin inflammation shares many characteristics of epidermal regeneration during wound healing, we also studied GATA3 expression under such conditions. Psoriatic lesional skin showed decreased GATA3 mRNA and protein expression compared to non-lesional skin. GATA3 expression was also markedly decreased in inflamed skin of mice with a psoriasiform dermatitis induced with imiquimod. Tape-stripping of non-lesional skin of patients with psoriasis, a standardized psoriasis-triggering and skin regeneration-inducing technique, reduced the expression of GATA3. In wounded skin of mice, low GATA3 mRNA and protein expression was detected. Taken together, GATA3 expression is downregulated under regenerative and inflammatory hyperproliferative skin conditions. GATA3 expression could be re-induced by successful narrow-band UVB treatment of both human psoriasis and imiquimod-induced psoriasiform dermatitis in mice. The prototypic Th2 cytokine IL-4 was the only cytokine capable of inducing GATA3 in skin explants from healthy donors. Based on these findings we argue that GATA3 serves as a key regulator in psoriatic inflammation, keratinocyte hyperproliferation and skin barrier dysfunction. Cellular and molecular effects of pulsed dye laser and local narrow-band UVB therapy in psoriasishttp://repub.eur.nl/pub/27778/
Mon, 01 Mar 2010 00:00:01 GMT<div>E. Rácz</div><div>J. de Leeuw</div><div>E.M. Baerveldt</div><div>M. Kant</div><div>H.A.M. Neumann</div><div>L. van der Fits</div><div>E.P. Prens</div>
Background and Objectives: Pulsed dye laser (PDL) therapy is effective in clearing psoriasis plaques, but the mechanism of action is only partially understood. Local narrow-band ultraviolet B (NB-UVB), which has a better-defined mode of action, is an effective standard treatment for psoriasis. Our aim was to evaluate the cellular and molecular effects of PDL and to compare them with those of local NB-UVB in order to gain further insight into their mechanisms of action in psoriasis. Study Design/Patients and Methods: Nineteen patients with stable plaque-type psoriasis were treated either with PDL or NB-UVB. Lesional punch biopsies were obtained from all patients before treatment. Additional biopsies were obtained at 3 and 24 hours after PDL treatment in five of these patients. In 14 patients additional biopsies were taken after 7 and 13 weeks of treatment. Samples were histopathologically examined for the level of dermal T cell infiltrate, and the expression of epidermal β-defensin 2, immune cell-derived tumor necrosis factor (TNF)-α, endothelial E-selectin, vascular endothelial growth factor receptor (VEGFR) 2 and 3, and the expression of interleukin (IL)-23 before and after treatment. Results: The expression of VEGFR2, VEGFR3, and E-selectin was decreased in clinically high responders within 24 hours after PDL treatment. The expression of IL-23, TNF-α mRNA, and E-selectin protein were significantly reduced after two PDL treatments, whereas the expression of all epidermal markers and dermal T cell infiltrates had normalized after four treatments. The expression of epidermal activation markers and E-selectin were significantly reduced after 13 weeks of NB-UVB treatment. Conclusions: The expression of epidermal activation markers and the dermal T cell infiltrates were decreased after both treatments. The decreased expression of VEGFR2 and VEGFR3 followed by the down-regulation of TNF-α and IL-23p19 may be contributory factors in the efficacy of PDL in stable plaque-type psoriasis.